Kinetic resolution of 1,2-diols through highly site- and enantioselective catalytic silylation

Article abstract of DOI:10.1002/anie.200703650

(Chemical Equation Presented) Resolved to silylate: A chiral silylation catalyst is used for kinetic resolution of three classes of acyclic 1,2-diols. The catalyst differentiates, with excellent precision, between the two hydroxy groups of a substrate. The majority of the diols, obtained in high enantiomeric purity, cannot be accessed with similar stereochemical purity through catalytic asymmetric dihydroxylation.

Full text of DOI:10.1002/anie.200703650

Angewandte
Chemie
DOI: 10.1002/anie.200703650
Asymmetric Catalysis
Kinetic Resolution of 1,2-Diols through Highly Site- and
Enantioselective Catalytic Silylation**
Yu Zhao, Aurpon W. Mitra, Amir H. Hoveyda,* and Marc L. Snapper*
1,2-Diols are components of a variety of biologically active
molecules; facile access to this class of building blocks in high
enantiomeric purity is thus an important objective.[1] Catalytic
protocols delivering diols that are not available through
asymmetric dihydroxylation[2] (e.g., syn-1,2-diol products
from cis alkenes)[2,3] and which furnish differentiated hydroxy
groups are particularly desirable. We have developed an
efficient method for kinetic resolution[4] of three classes of
acyclic 1,2-diols through catalytic asymmetric silylation.[5,6]
Enantioselective silylation of a chiral 1,2-diol is more
complex than that of the related meso isomers[5] and
necessitates a higher degree of precision from the chiral
catalyst. An effective kinetic resolution, as expected, must
involve preferable reaction with one enantiomer of the
substrate (rate of a!b @ ent-a!ent-b; Scheme 1). This class
difference in size between RS and RL (Scheme 1), the more
discriminating the catalyst needs to be.
We began by studying the kinetic resolution of rac-2a
(Table 1). Catalyst 1, a small molecule (MW= 308.5 gmolꢀ1)
that was recently identified to be effective in promoting
Table 1: Initial studies on catalytic kinetic resolution of diol 2a.[a]
[b]
Entry T [8C];
Conv. [%][b]
3a:4a[c] Recovered 2a
ee [%][c]
Product 3a
ee[%][c]
krel
1
2
3
4
4; 61
>98:<2 70
>98:<2 82
>98:<2 38
>98:<2 34
45
71
88
93
5
ꢀ15; 53
ꢀ30; 30
ꢀ50; 27
16
24
35
[a] Conditions: 1.0m in diol, 1.25 equiv N,N-diisopropylethylamine
(DIPEA), 1.0 equiv TBSCl. [b] Conversions and krel values calculated by
the methods of Kagan.[9] [c] Ratios of 3a:4a and ee values determined by
chiral GLC analysis (see the SupportingInformation for details).
Scheme 1. Effective kinetic resolution demands high site selectivity as
well as enantioselectivity. RS and RL are small and large R groups,
respectively. TBS=tert-butyldimethylsilyl.
enantioselective silylations of meso diols,[5] initiates asym-
metric silylation. Moderate selectivity is obtained at 48C
(Table 1, entry 1; krel = 5). At lower reaction temperatures,
selectivity increases (Table 1, entries 1–4), and, at ꢀ508C,
catalytic resolution proceeds with krel = 35 (Table 1, entry 4).
In all cases, the silyl ether derived from reaction of the more
hindered carbinol is not detected (< 2% by GLCanalysis). [8]
Further investigations allowed us to establish conditions that
provide 2a in 96% ee and 44% yield after purification (see
Table 2, entry 1).
of transformations, however, demands an additional and
critical attribute: it is imperative that silylations proceed with
high site selectivity[7] (rate of a!b @ a!ent-c; Scheme 1).
Kinetic resolution of a 1,2-diol, therefore, does more than
challenge a catalystꢀs ability to promote preferential silylation
of one enantiomer; it illustrates the extent to which a catalyst
can differentiate between two hydroxy sites—the smaller the
A variety of syn-1,2-diols can be catalytically resolved
(Table 2); selectivities are usually at useful levels (krel > 10).[10]
Several additional points merit mention: 1) Reactions pro-
ceed with high site selectivity; in most cases, little (3% and
2% in Table 2, entries 4 and 5, respectively) or none of the
isomeric silyl ether 4 is generated (< 2% in Table 2, entries 1–
3, and 6). Only with substrates bearing a carboxylic ester
(Table 2, entries 7 and 8) is 14% of isomer 4 formed (see
below for further discussion). 2) As a result of high site
selectivities, unreacted diols and silyl ethers are obtained in
useful yields. Under the conditions shown in Table 2, designed
for maximal unreacted substrate enantiomeric purity, syn-1,2-
diols are recovered in 30–48% yield and in 87 to > 98% ee.
3) The selectivity (97:3 site selectivity; krel = 29) in Table 2,
[*] Y. Zhao, A. W. Mitra, Prof. A. H. Hoveyda, Prof. M. L. Snapper
Department of Chemistry
Merkert Chemistry Center
Boston College
Chestnut Hill, MA 02467 (USA)
Fax: (+1)617-552-1442
E-mail: amir.hoveyda@bc.edu
marc.snapper@bc.edu
[**] Financial support was provided by the NIH (GM-57212); Y.Z. and
A.W.M. were supported by LaMattina graduate and Kozarich
undergraduate fellowships, respectively.
Supportinginformation for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2007, 46, 8471 –8474
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Table 2: Kinetic resolution of secondary alcohols by catalytic asymmetric silylation.[a]
an Et (Table 2, entry 4) and a car-
boxylic ester unit, and the results in
entries 7 and 8 (Table 2) are nearly
identical (i.e., the difference in size
between a CO2Et and a CO2tBu
makes little or no difference in site
selectivity). It is, however, plausible
that intramolecular hydrogen bond-
ing involving the more Lewis basic
(vs. ketone) ester carbonyl and the
adjacent OH enhances a-hydroxy
nucleophilicity. Alternatively, the
Lewis basic carbonyl may be
involved in activation[5,12] of the
silyl chloride (hexacoordinated
silane) and delivery of the silyl
chloride to the proximal alcohol.[13]
5) The protocol delivers chiral diols
T [8C]; 3:4[c]
Recovered 2
Product 3
krel
[b]
Entry Recovered
Equiv. 1;
diol (2)
Conv. [%][b] t [h]
yield [%][d]; ee [%][c] yield [%][d]
ee [%][c]
;
ꢀ50;
1
2
3
4
5
0.3; 55
72
>98:<2 44; 96
48; 81
50; 88
68; 39
50; 73
45; 71
35
48
8
ꢀ50;
0.3; 51
48
>98:<2 48; 91
>98:<2 30; 96
ꢀ15;
0.3; 70
72
ꢀ40;
that might otherwise require
lengthier synthetic route to prepare.
Synthesis of dihydroxy-
a
0.3; 57
48
97:3
98:2
36; 98
34; 91
29
17
ꢀ40;
butanoates (Table 2, entries 7 and
8), previously obtained by multistep
manipulation of substrates obtained
from the chiral pool, is a case in
point.[14] 6) Although yields of the
isolated products are lower in this
resolution process than in the alter-
native asymmetric dihydroxylation,
higher enantioselectivities can be
obtained. For example, catalytic
asymmetric dihydroxylation affords
the diols in entries 2 and 3 (Table 2)
in only 56 and 72% ee, respec-
tively.[2]
0.3; 57
48
ꢀ30;
6
0.3; 55
24
>98:<2 44; >98
52; 80
>50
ꢀ30;
7
8
0.3; 64
72
86:14 32; 87
86:14 34; 90
34; 78[e]
44; 77[g]
25[f]
ꢀ30;
0.3; 65
25[f]
72
[a] Conditions: see Table 1 and the SupportingInformation for details. [b, c] See Table 1. [d] Yields of
isolated material. [e] Minor silyl ether isomer was isolated in 6% yield with 82% ee. [f] krel calculated on
the basis of eersm and ee of major product isomer (see reference [9]). [g] Minor silyl ether isomer was
isolated in 8% yield and 88% ee.
Catalytic asymmetric silylation
of primary alcohols that are adja-
cent to a secondary or a tertiary
entry 4 indicates the highly discriminating nature of 1.[11]
Accordingly, the corresponding diol that carries an Et and
an iPr group undergoes less than 2% conversion. 4) Reac-
tions in Table 2, entries 7 and 8 proceed with lower site
selectivity (86:14) than the reaction with ketone 2e (Table 2,
entry 5) and are mechanistically informative. The slower
reacting enantiomer is predominantly involved in the for-
mation of the minor silyl ether, which may form through
complex II (vs. I, Figure 1). It is unlikely that reaction via II is
caused by steric factors; there is little size difference between
carbinol constitutes another synthetically useful class of
transformations (Table 3). Reactions of diols bearing a
secondary (Table 3, entries 1–3)[15] as well as those that
carry a tertiary (entries 4–6) carbinol proceed with excep-
tional site selectivity (> 98% primary silyl ether); krel values
of 12 to greater than 50 are obtained, except for the
transformation in entry 1 (krel = 8). The findings in Table 3
point to the general trend that particularly efficient processes
can be expected with substrates that carry a more sterically
demanding secondary or tertiary alcohol (Table 3, entry 1 vs.
2 and 3 and entry 4 vs. 5 and 6). It should be noted
that catalytic asymmetric dihydroxylations of 1,1-
disubstituted olefins that bear aliphatic substituents
typically proceed in less than 90% ee.[2]
Enantioselective silylations are simple to per-
form. The structurally robust catalyst is easy to
prepare and commercially available (Aldrich);
commercially available silyl chloride is utilized as
well (no purification), and reactions can be carried
out in air. Racemic substrates can be accessed on a
gram scale and used in catalytic asymmetric
Figure 1. Transition-state models that account for lower site selectivity of ester-
containingsubstrates.
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Angew. Chem. Int. Ed. 2007, 46, 8471 –8474

Angewandte
Chemie
Table 3: Kinetic resolution of 1,2-diols bearinga primary alcohol. [a]
have
significant
implications
regarding chiral catalyst and syn-
thetic-method design and develop-
ment; investigations along these
lines are in progress.
[b]
Entry Recovered diol Equiv. 1;
T [8C]; Recovered 5/6
t [h]
Product
krel
Received: August 9, 2007
Published online: September 26, 2007
Conv.[%][b]
yield [%][d]; ee [%][c]
yield [%][d]; ee [%][c]
ꢀ78;
Keywords: asymmetric catalysis ·
diols · enantioselective synthesis ·
kinetic resolution · silylation
1
2
0.2; 56
0.2; 55
38; 74
46; 57
55; 68
8[e]
24
.
ꢀ78;
25; 84
14[e]
24
[1] a) I. Marko, J. S. Svendsen, Com-
prehensive Asymmetric Catalysis
(Eds.: E. N. Jacobsen, A. Pfaltz,
H. Yamamoto), Springer, New
York, 1999, pp. 713 – 787; b) For a
recent example, see: J. B. Morgan,
S. P. Miller, J. P. Morken, J. Am.
Chem. Soc. 2003, 125, 8702 – 8703.
[2] H. C. Kolb, M. S. VanNieuwenhze,
K. B. Sharpless, Chem. Rev. 1994,
94, 2483 – 2547.
[3] L. Wang, K. B. Sharpless, J. Am.
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[4] E. Vedejs, M. Jure, Angew. Chem.
2005, 117, 4040 – 4069; Angew.
Chem. Int. Ed. 2005, 44, 3974 –
4001, and references therein.
ꢀ78;
3
4
5
6
0.2; 55
0.3; 52
0.3; 54
0.2; 52
42; >98
42;[f] 94
44; >98
45; >98
44; 76
50; 58
52; 84
49; 91
>50
12
24
ꢀ78;
96
ꢀ78;
>50
>50
40
ꢀ78;
24
[a–d] See Tables 1 and 2; >98% primary silyl ether observed in all cases. [e] The ee values for these cases
have ꢁ5% margin of error (krel values have error bars of ꢁ1). [f] Small amount of product de-silylation
upon purification causes slightly higher than expected recovered starting material (rsm) yield.
[5] Y. Zhao, J. Rodrigo, A. H. Hov-
eyda, M. L. Snapper, Nature 2006, 443, 67 – 70.
silylation; the examples in Equations (1) and (2) illustrate this
point. By adjustment of conversion, silyl ethers are obtained
[6] For kinetic resolution of indan-1-ol through silylation reactions
promoted by stoichiometric quantities of a chiral catalyst (3–
14 days, substrate recovered with up to 70% ee), see: a) T. Isobe,
K. Fukuda, Y. Araki, T. Ishikawa, Chem. Commun. 2001, 243 –
244; for Cu-catalyzed kinetic resolution of 2-pyridyl-substituted
benzylic secondary alcohols through reactions with a chiral silyl
hydride (up to 80% ee), see: b) S. Rendler, G. Auer, M.
Oestreich, Angew. Chem. 2005, 117, 7793 – 7797; Angew. Chem.
Int. Ed. 2005, 44, 7620 – 7624.
[7] For examples of highly site-selective catalytic acylation reac-
tions, see: C. Lewis, S. J. Miller, Angew. Chem. 2006, 118, 5744 –
5747; Angew. Chem. Int. Ed. 2006, 45, 5616 – 5619.
[8] When N-methylimidazole is used as the catalyst (at ꢀ508C), rac-
3a is formed with > 20:1 site selectivity.
[9] H. B. Kagan, J. C. Fiaud, Top. Stereochem. 1988, 18, 249 – 330.
[10] Catalytic kinetic resolutions of anti-1,2-diols are less selective
(krel < 3) but, in contrast to reactions of syn-1,2-diols, have been
the subject of several previous reports: a) Y. Matsumura, T.
Maki, S. Murakami, O. Onomura, J. Am. Chem. Soc. 2003, 125,
2052 – 2053; b) C. Mazet, S. Roseblade, V. Kꢁhler, A. Pfaltz, Org.
Lett. 2006, 8, 1879 – 1882.
[11] For catalytic asymmetric reactions involving differentiation of a
Me and Et substituent, see: a) G. T. Copeland, S. J. Miller, J. Am.
Chem. Soc. 2001, 123, 6496 – 6502; b) R. I. Storer, D. E. Carrera,
Y. Ni, D. W. C. MacMillan, J. Am. Chem. Soc. 2006, 128, 84 – 86;
c) K. Arai, M. M. Salter, Y. Yamashita, S. Kobayashi, Angew.
Chem. 2007, 119, 973 – 975; Angew. Chem. Int. Ed. 2007, 46, 955 –
957.
in high enantioselectivity and yield. As an example, silyl ether
7 is isolated in 45% yield and 98% ee (45% conversion) when
the reaction is performed at 1.0m (vs. 1.4m for substrate
recovery; see the Supporting Information for details).
The studies outlined herein furnish, to the best of our
knowledge, the first efficient method for kinetic resolution of
syn-1,2-diols (Table 2) and vicinal diols that bear a tertiary
alcohol (Table 3, entries 4–6). The findings disclosed herein
enhance the utility of catalytic asymmetric silylation by
demonstrating that chiral catalyst 1 is able to provide
excellent site- as well as enantioselectivity. Such attributes
[12] S. E. Denmark, G. L. Beutner, T. Wynn, M. D. Eastgate, J. Am.
Chem. Soc. 2005, 127, 3774 – 3789, and references therein.
[13] N-methylimidazole affords a 4:1 mixture of isomers, perhaps as a
result of the same factors. Catalytic asymmetric silylation of the
more Lewis basic nBu amide affords silyl ether isomers in 1:4.4
Angew. Chem. Int. Ed. 2007, 46, 8471 –8474
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www.angewandte.org
8473

Communications
ratio (OSiR3 a to amide is predominant; 46% ee); the low
ee value may be the result of (noncatalytic) amide-directed
silylation.
[15] For alternative approaches to catalytic kinetic resolutions of 1,2-
diols bearing a primary and a secondary carbinol, see: a) F.
Iwasaki, T. Maki, O. Onomura, W. Nakashima, Y. Matsumura, J.
Org. Chem. 2000, 65, 996 – 1002; b) S. E. Schaus, B. D. Brandes,
J. F. Larrow, M. Tokunaga, K. B. Hansen, A. E. Gould, M. E.
Furrow, E. N. Jacobsen, J. Am. Chem. Soc. 2002, 124, 1307 –
1315; and reference [10b].
[14] a) S. M. Mahalingam, N. Sathyamurthy, I. S. Aidhen, Adv. Synth.
Catal. 2005, 347, 715 – 717; For a chiral auxiliary approach, see:
b) D. J. Dixon, S. V. Ley, A. Polara, T. Sheppard, Org. Lett. 2001,
3, 3749 – 3752.
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Angew. Chem. Int. Ed. 2007, 46, 8471 –8474